Retrieval systems and related methods

ABSTRACT

Drug delivery articles, resident articles, and retrieval systems e.g., for gram-level dosing, are generally provided. In some embodiments, the articles are configured for transesophageal administration, transesophageal retrieval, and/or gastric retention to/in a subject. In certain embodiments, the article includes dimensions configured for transesophageal administration with a gastric resident system. In some cases, the article may be configured to control drug release e.g., with zero-order drug kinetics with no potential for burst release for weeks to months. In some embodiments, the articles described herein comprise biocompatible materials and/or are safe for gastric retention. In certain embodiments, the article includes dimensions configured for transesophageal retrieval. In some cases, the articles described herein may comprise relatively large doses of drug (e.g., greater than or equal to 1 gram).

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Patent Application Ser. No. 62/678,492, filed May 31, 2018,entitled “DRUG DELIVERY ARTICLES FOR GRAM-LEVEL DOSING,” to U.S.Provisional Patent Application Ser. No. 62/817,477, filed Mar. 12, 2019,entitled “DRUG DELIVERY ARTICLES FOR GRAM-LEVEL DOSING,” to U.S.Provisional Patent Application Ser. No. 62/678,471, filed May 31, 2018,entitled “RESIDENT ARTICLES FOR GRAM-LEVEL DOSING,” and to U.S.Provisional Patent Application Ser. No. 62/678,439, filed May 31, 2018,entitled “RETRIEVAL SYSTEMS AND RELATED METHODS,” each of which isincorporated herein by reference in its entirety for all purposes.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with Government support under Grant No. R37EB000244 awarded by the National Institutes of Health (NIH). TheGovernment has certain rights in the invention.

FIELD

The present invention generally relates to drug delivery components andresident articles for gram-level dosing. In some embodiments, retrievalsystems are provided.

BACKGROUND

Drug adherence to indefinite duration oral therapy is often poor. Recentadvances in developing gastric resident systems for long-term drugdelivery of medication are addressing the challenge of medicationadherence with swallowable systems. However, challenges for these drugdelivery devices include, for example, achieving high levels of drugloading, controlling the release rate of drug for an extended period,and preventing the burst release of drug. Additionally, adherence ratesto oral therapies for chronic asymptomatic conditions are estimated tobe less than 50%. Current pharmacologic solutions to the adherenceproblem are limited to invasive devices and a restricted subset ofpharmacologic agents. Furthermore, extended release orally administereddrug delivery systems are limited by the quantity of drug that can fitinside the largest ingestible capsule and therefore cannot be used totreat many diseases with long and frequent dosing regimens.

Accordingly, improved systems, articles and methods are needed.

SUMMARY

The present invention generally relates to drug delivery components andresident articles for gram-level dosing. In some embodiments, retrievalsystems are provided.

In one aspect, articles configured for transesophageal administration,transesophageal retrieval, and/or gastric retention are provided. Insome embodiments, the article comprises a polymer matrix comprising apolymeric material and a therapeutic agent associated with the polymermatrix and a hollow core disposed within the polymeric matrix andconfigured to receive an elastic wire.

In some embodiments, the article comprises a polymeric material having areconfigurable shape and a hollow core and a therapeutic agentassociated with the polymeric material, wherein the article has amaximum dimension of greater than or equal to 28 cm and wherein thetherapeutic agent is present in the article in an amount greater than orequal to 3 grams.

In another aspect, systems configured for transesophageal retrieval areprovided. In some embodiments, the system comprises a polymericcomponent having a flexible member, a binding component associated withan end portion of the polymeric component, and a sensor associated withan end portion of the polymeric component, wherein the system isconfigured to pass through a nasogastric and/or endoscopic tube.

In another aspect, methods for retrieving a gastric residence systemlocated internal to a subject are provided. In some embodiments, themethod comprises administering transesophageally to a subject a system,the system comprising a polymeric component having a flexible member anda binding component associated with an end portion of the polymericcomponent, determining, via a sensor associated with an end portion ofthe polymeric component, a distance between the binding component andthe gastric residence system, interfacing, via a locking mechanismassociated with an end portion of the polymeric component, the gastricresidence system, and removing, transesophageally, the gastric residencesystem from the location internal to the subject.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument Incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIG. 1A is a schematic illustration of an exemplary article, accordingto one set of embodiments;

FIG. 1B shows an exemplary article, according to one set of embodiments;

FIG. 1C shows a scanning electron microscopy image of drug crystals onthe surface of an exemplary article, according to one set ofembodiments;

FIG. 1D shows an exemplary article, according to one set of embodiments;

FIG. 2A shows an exemplary formation of an exemplary article, accordingto one set of embodiments;

FIG. 2B shows an exemplary setup for forming an exemplary article,according to one set of embodiments;

FIG. 2C shows an exemplary article, according to one set of embodiments;

FIG. 3A is a plot of cumulative percent drug released versus time(days), according to one set of embodiments;

FIG. 3B is a plot of concentration in ng/mL versus time (days),according to one set of embodiments;

FIG. 4A is a photograph of an uncoated versus coated article, accordingto one set of embodiments;

FIG. 4B is a photograph of an exemplary coated article, according to oneset of embodiments;

FIG. 4C is a photograph of an exemplary coated article, according to oneset of embodiments;

FIG. 4D is a plot of cumulative percent drug released versus time(days), according to one set of embodiments;

FIG. 5A is a plot of cumulative percent drug released versus time(days), according to one set of embodiments;

FIG. 5B is a plot of cumulative percent drug released versus time(days), according to one set of embodiments;

FIG. 6 is a schematic illustration of an exemplary article, according toone set of embodiments;

FIG. 7 is a schematic illustration of an exemplary article, according toone set of embodiments;

FIGS. 8A-8D show the design and in vivo evaluation of a large-dosegastric residence system (GRS) for drug delivery, according to one setof embodiments. (FIG. 8A) (i-ii) An NG tube is first placed as a conduitfor the large-dose GRS to be non-surgically administered, and then theNG tube is removed from the patient. (iii-iv) The GRS resides in thegastric cavity while releasing drugs. (v-vi) An NG tube is again placedin the patient for deployment of a retrieval device to attach and removethe GRS from the gastric cavity. Black arrows indicate direction ofmovement of the NG tube and retrieval device, and red arrows indicatedrug release. (FIG. 8B) The GRS consists of a series of drug pills on acoiled superelastic nitinol wire; the ends are protected with a retainerand tubing. (FIG. 8C) Representative radiographs of the GRS immediatelyafter deployment and on day 28 in a swine model. Dashed circles indicateGRS location. (FIG. 8D) The retrieval device consists of a Hall effectsensor and a magnet that can detect and attach to the magnets on eitherend of the GRS. Representative stepwise radiographs of the retrievalprocess executed in a swine model are shown below. Dashed circlesindicate coupling of retrieval device with GRS. The components of bothends of the GRS [glue, a retainer, and a poly(ε-caprolactone) (PCL)plug] are also shown;

FIGS. 9A-9G show fabrication and in vitro release of TB antibiotics fromindividual drug pills, according to one set of embodiments. (FIG. 9A)Coated drug pills are made by mixing drug with silicones and extractingindividual pills from the homogeneous matrix using a biopsy punch beforespray-coating pills in a pan coater. A schematic visualization and across-sectional image of the Eudragit RS 100-coated doxycycline hyclatepill are shown. (FIG. 9B) In vitro release of doxycycline hyclate from adrug pill in SGF with formulations including different concentrations ofPEG and Eudragit RS 100 coatings. (FIG. 9C) In vitro release ofisoniazid from a drug pill in water. (FIG. 9D) In vitro release ofethambutol from a drug pill in SGF. (FIG. 9E) In vitro release ofpyrazinamide from a drug pill in SGF. (FIG. 9F) In vitro release ofmoxifloxacin from a drug pill in SGF. (FIG. 9G) In vitro release ofrifampicin in water from devices with 2 g of drug and 0% PEG. Inset:Image of the rifampicin-loaded device. Error bars represent SD for n=3samples in each group;

FIGS. 10A-10D show in vivo release of doxycycline hyclate from the GRSin a swine model, according to one set of embodiments. (FIG. 10A)Representative photograph of a GRS after assembly of drug pills along anitinol wire before deployment in vivo. (FIG. 10B) Representative photoof a retrieved GRS after 28 days in vivo in a swine model. (FIG. 10C)Left: Concentration-time profiles of doxycy-cline hyclate in serum afteradministering a single dose of 100 mg (n=3). Right: Concentration-timeprofiles of doxycycline hyclate in serum after administering the GRS,which had 10 g of drug across four formulations (n=3; FIG. S5). (FIG.10D) Area under the curve (AUC) and the duration of drug release for asingle dose compared to the formulations of the GRS administered invivo, with the mean value and SD reported for n=3 samples in each group;

FIGS. 11A-11D. shows physical parameters of the GRS as the drug weightincreases, according to one set of embodiments. (FIG. 11A) Diagram ofthe GRS and plot of height of device versus drug weight. The coil heightis fixed at 4 mm due to the size of the measured drug pill height, andthe diameter of the overall GRS is kept constant at 104 mm based on thesize of the nitinol fixture (n=3). (FIG. 11B) The calculated height ofthe GRS as a function of the drug weight, calculated by the number ofpills that can fit on a single coil based on measurements of the pillheight and diameter of the GRS. The number of coils is discrete; betweena certain range of drug weight, the height of the device generallyremains the same. (FIG. 11C) The calculated overall end-to-end length ofthe uncoiled GRS according to the drug weight. (FIG. 11D) The calculatedtotal GRS weight according to the drug weight, incorporating the weightof the polymer matrix, nitinol wire, and ends of the device;

FIG. 12. shows serial radiographs of the GRS over 1 month in a swinemodel, according to one set of embodiments. Radiographs of the gastriccavity were taken every few days over the course of 1 month to monitorfor safe long-term gastric residence of the GRS. The dotted linesencircle the GRS in the gastric cavity of the swine;

FIGS. 13A-13C. shows effect of the GRS on the weight and stomach tissueof swine, according to one set of embodiments. (FIG. 13A) The animals'weight was measured every week from when it was brought into the animalfacility until when it was euthanized. Week 0 denotes the week that theGRS was administered to the gastric cavity of the animal. At the end ofweek 4, the GRS was retrieved from the gastric cavity, and the animal iseither euthanized immediately or is used for other studies with theweight being measured every week. (FIG. 13B) After 2 weeks of gastricresidence for the GRS, the stomach mucosa was assessed for any damage. Arepresentative hematoxylin and eosin stain of stomach tissue at week 0(prior to deployment of the GRS) and at week 2 (when the GRS isretrieved and the animal is euthanized) is shown (n=3). (FIG. 13C)Representative macroscopic image of the stomach tissue at the end ofweek 2 when a GRS was retrieved from the gastric cavity and the animalis euthanized to assess any damage to the mucosa (n=3);

FIGS. 14A-14B. shows hall effect sensor acid stability and retrievalusing an in vitro stomach model, according to one set of embodiments.(FIG. 14A) Voltage reading of the Hall effect sensor before and aftersubmersion in simulated gastric fluid. Error bars represent the standarddeviation for n=3 samples in each group. (FIG. 14B) Photograph of athree-dimensional printed stomach model used to test sensing andmagnetic attachment of the retrieval device to the gastric residentsystem;

FIGS. 15A-15B. shows in vivo formulations and their corresponding 4-weekin vitro drug release profiles of doxycycline hyclate-silicone pills ofthe 10 g GRS, according to one set of embodiments. (FIG. 15A) Table ofin vivo formulations for the doxycycline hyclate-silicone pills of the10 gram GRS assembled 1 gram of formulation 1, 2 grams of formulation 2,3 grams of formulation 3, and 4 grams of formulation 4. Formulation 1contained poly(ethylene glycol) (PEG), whereas the others did not. Alldrug pills were coated with either Eudragit RS 100 (formulations 1 and2) or with poly(ε-caprolactone) (PCL) (formulations 3 and 4). (FIG. 15B)In vitro release profiles of doxycycline hyclate from drug-siliconepills over 4 weeks in simulated gastric fluid;

FIG. 16. shows in vivo release of rifampicin from the GRS in a swinemodel, according to one set of embodiments. A GRS with 2 grams ofrifampicin formulated with 54% rifampicin and 46% silicone wasadministered to a swine model for 7 days, and the serum concentrationsof rifampicin were recorded;

FIGS. 17A-17F. shows field questionnaire results at TB clinics,according to one set of embodiments. (FIG. 17A) Table of optionspresented to TB health care providers and patients with TB regardingfour different methods of improving patient adherence to treatment.(FIG. 17B) Responses from health care providers on how they wouldallocate rupees towards four different options to improve patientadherence to treatment. (FIG. 17C) Responses from patients on whethereach option would help them adhere to treatment. (FIG. 17D) Table ofoptions presented to TB health care providers and patients with TBregarding three different routes of administering a long-term gastricresident device for TB treatment. (FIG. 17E) Responses from health careproviders on the feasibility of three different routes of administrationwith respect to the time each option would take in a TB clinic. (FIG.17F) Responses from patients on their willingness to try three differentroutes of administration for a long-lasting gastric resident device forTB treatment;

FIGS. 18A-18C shows field questionnaire results on NG tube deployment atTB clinics, according to one set of embodiments. (FIG. 18A) Responsesfrom all TB health care providers on their experience with inserting aNG tube previously. (FIG. 18B) Responses from all TB health careproviders on whether they agree with using a NG tube for deploying TBtreatment. (FIG. 18C) Responses from all TB health care providers onwhether their hospital or clinic has the infrastructure to insert NGtubes in TB patients;

FIG. 19A is a photograph of an exemplary article in a straight (first)configuration, according to one set of embodiments;

FIG. 19B is a photograph of an exemplary article in a secondconfiguration, according to one set of embodiments;

FIG. 19C is an x-ray of an exemplary article in the stomach of asubject, according to one set of embodiments;

FIG. 19D is an x-ray of an exemplary article in the stomach of asubject, according to one set of embodiments;

FIG. 20A is a photograph of an exemplary article in a straight (first)configuration, according to one set of embodiments;

FIG. 20B is a photograph of an exemplary article in a secondconfiguration, according to one set of embodiments;

FIG. 21A is a schematic illustration of an exemplary article in aparticular configuration, according to one set of embodiments;

FIG. 21B is an x-ray of an exemplary article in the stomach of asubject, according to one set of embodiments;

FIG. 21C is an x-ray of an exemplary article in the stomach of asubject, according to one set of embodiments;

FIG. 22 is a schematic illustration of an exemplary article in aparticular configuration, according to one set of embodiments;

FIG. 23 is a schematic illustration of administration of an exemplaryarticle, according to one set of embodiments;

FIG. 24A is a schematic illustration of an exemplary system, accordingto one set of embodiments;

FIGS. 24B-24E are x-ray images of an exemplary retrieval system used toa retrieve a gastric residence system from the stomach of a subject,according to one set of embodiments;

FIGS. 25A-25C are schematic illustrations of an exemplary retrievalsystem configured to retrieve a gastric residence system, according toone set of embodiments;

FIG. 25D is a photograph of an exemplary retrieval system, according toone set of embodiments;

FIG. 25E is an x-ray image of an exemplary retrieval system (FIG. 25D)used to a retrieve a gastric residence system from the stomach of asubject, according to one set of embodiments;

FIG. 26A is photograph of a locking mechanism, according to one set ofembodiments;

FIG. 26B is a plot of total impulse versus barb angle, according to oneset of embodiments;

FIG. 27A is a schematic illustration of an exemplary system, accordingto one set of embodiments; and

FIG. 27B is a photograph of an exemplary system, according to one set ofembodiments.

DETAILED DESCRIPTION

Drug delivery components and resident articles for gram-level dosing aregenerally provided. Retrieval systems and related methods are alsoprovided.

In some embodiments, the articles are configured for transesophagealadministration, transesophageal retrieval, and/or gastric retentionto/in a subject. Advantageously, the articles described herein maycomprise relatively high levels of drug loading and stability (e.g.,greater than or equal to 1 gram), obtain gastric retention forrelatively long periods of time, and/or may be compatible with a broadrange of drug classes. In certain embodiments, the article includesdimensions configured for transesophageal administration with a gastricresident system. In some cases, the article may be configured to controldrug release e.g., with zero-order drug kinetics with no potential forburst release for weeks to months. In some embodiments, the articlesdescribed herein comprise biocompatible materials and/or are safe forgastric retention. In certain embodiments, the article includesdimensions configured for transesophageal retrieval. In some cases, thearticles described herein may comprise relatively large doses of drug(e.g., greater than or equal to 1 gram).

A “subject” refers to any animal such as a mammal (e.g., a human).Non-limiting examples of subjects include a human, a non-human primate,a cow, a horse, a pig, a sheep, a goat, a dog, a cat or a rodent such asa mouse, a rat, a hamster, a bird, a fish, or a guinea pig. Generally,the invention is directed toward use with humans.

In some embodiments, the article comprises a polymer matrix (e.g.,comprising a polymeric material) and a therapeutic agent associated withthe polymer matrix. For example, as illustrated in FIG. 1A, exemplaryarticle 100 comprises polymer matrix 110. In certain embodiments,article 100 comprises hollow core 120 disposed within polymer matrix110. In some embodiments, the hollow core disposed within the polymericmatrix is configured to receive an elastic wire.

In certain embodiments, the therapeutic agent is disposed within thepolymer matrix. In some embodiments, the therapeutic agent is adjacentthe polymer matrix. As used herein, when a component is referred to asbeing “adjacent” another component, it can be directly adjacent to(e.g., in contact with) the component, or one or more interveningcomponents also may be present. A component that is “directly adjacent”another component means that no intervening component(s) is present. Insome cases, the therapeutic agent may be directly adjacent the polymermatrix (e.g., as a layer deposited on the polymer matrix).

In some embodiments, the polymer matrix comprises a plurality of holes(e.g., microdrilled holes in the polymer matrix). In some embodiments,the plurality of holes have an average diameter of greater than or equalto 0.1 mm, greater than or equal to 0.2 mm, greater than or equal to 0.5mm, greater than or equal to 0.7 mm, greater than or equal to 0.8 mm, orgreater than or equal to 0.9 mm. In certain embodiments, the pluralityof holes have an average diameter of less than or equal to 1 mm, lessthan or equal to 0.9 mm, less than or equal to 0.7 mm, less than orequal to 0.5 mm, or less than or equal to 0.2 mm. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 0.1 mm and less than or equal to 1 mm). Other ranges are alsopossible.

In certain embodiments, the polymeric matrix comprises a polymericmaterial. In some embodiments, the polymeric material is selected fromthe group consisting of vinylpolysiloxane, polydimethylsiloxane,polycaprolactone, polyethylene, polyethylene-vinyl acetate,methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose, ethylhydroxyethylcellulose,sodium-carboxymethylcellulose, ethylcellulose, hypromellose acetatesuccinate, cellulose acetate, cellulose acetate propionate, andcombinations thereof.

The polymeric material may have any suitable Young's elastic modulus. Insome embodiments, the Young's elastic modulus of the polymeric materialis less than or equal to 10 MPa, less than or equal to 8 MPa, less thanor equal to 6 MPa, less than or equal to 4 MPa, less than or equal to 2MPa, less than or equal to 1 MPa, or less than or equal to 0.8 MPa. Incertain embodiments, the Young's elastic modulus of the polymericmaterial is greater than or equal to 0.5 MPa, greater than or equal to0.8 MPa, greater than or equal to 1 MPa, greater than or equal to 2 MPa,greater than or equal to 4 MPa, greater than or equal to 6 MPa, orgreater than or equal to 8 MPa. Combinations of the above-referencedranges are also possible (e.g., greater than or equal to 0.1 MPa andless than or equal to 10 MPa). Other ranges are also possible.

In some embodiments, the article is selected to have a particulardiameter e.g., suitable for transesophageal administration and/ortransesophageal retrieval. In some embodiments, the article has adiameter of less than or equal to 20 mm, less than or equal to 15 mm,less than or equal to 10 mm, less than or equal to 8 mm, less than orequal to 6 mm, less than or equal to 4 mm, or less than or equal to 2mm. In certain embodiments, the article has a diameter of greater thanor equal to 1 mm, greater than or equal to 2 mm, greater than or equalto 4 mm, greater than or equal to 6 mm, greater than or equal to 8 mm,greater than or equal to 10 mm, or greater than or equal to 15 mm.Combinations of the above-referenced ranges are also possible (e.g.,greater than or equal to 1 mm and less than or equal to 10 mm, greaterthan or equal to 1 mm and less than or equal to 20 mm). Other ranges arealso possible.

In some embodiments, the article may have a particular maximum dimension(e.g., length) e.g., suitable for transesophageal administration and/ortransesophageal retrieval. In some embodiments, the maximum dimension ofthe article is greater than or equal to 5 mm, greater than or equal to 8mm, greater than or equal to 10 mm, greater than or equal to 15 mm,greater than or equal to 20 mm, greater than or equal to 25 mm, greaterthan or equal to 50 mm, greater than or equal to 100 mm, greater than orequal to 250 mm, greater than or equal to 500 mm, or greater than orequal to 750 mm. In certain embodiments, the maximum dimension of thearticle is less than or equal to 1000 mm, less than or equal to 750 mm,less than or equal to 500 mm, less than or equal to 250 mm, less than orequal to 100 mm, less than or equal to 50 mm, less than or equal to 25mm, less than or equal to 20 mm, less than or equal to 15 mm, less thanor equal to 10 mm, or less than or equal to 8 mm. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 5 mm and less than or equal to 1000 mm). Other ranges are alsopossible.

In some embodiments, the article may comprise a coating (e.g., to reduceor eliminate the burst release of a drug from the surface of thearticle). In some cases, the coating is adjacent (e.g., directlyadjacent) the polymer matrix. In certain embodiments, the coating isselected from the group consisting of Eudragit RS PO, Eudragit NM 30D,polycaprolactone, ethylcellulose, cellulose acetate, cellulose acetatebutyrate, polydimethysiloxane, polivinylacetate, and vinylpolysiloxane.Other coatings are also possible.

In certain embodiments, the article may comprise an excipient. In somecases, the excipient may be used to tune (e.g., change) the release rateof the drug (e.g., as compared to an article without such excipient). Insome embodiments, the excipient comprises polyethylene glycol and/orsilicone oil. In some cases, the polyethylene glycol has a numberaverage molecular weight of greater than or equal to 300 g/mol and lessthan or equal to 500,000 g/mol (e.g., greater than or equal to 400 g/moland less than or equal to 3,350 g/mol, greater than or equal to 400g/mol and less than or equal to 200,000 g/mol, greater than or equal to3,350 g/mol and less than or equal to 200,000 g/mol). Other ranges arealso possible.

In some embodiments, a magnetic component (e.g., a magnet) may beassociated with an end (e.g., an end surface) of the article. Suitablemagnetic materials include, for example, aluminum nickel cobalt alloys,ferrites, and neodymium-based materials. Such magnetic components may beuseful for, for example, retrieval of the article (e.g., from a locationinternal to the subject).

In certain embodiments, the article comprises a hollow core. In certainembodiments, the hollow core is configured to receive an elastic wire(e.g., comprising nitinol). In some embodiments, the elastic wirecomprises a superelastic alloy and/or shape memory material.

According to some embodiments, the composition and methods describedherein are compatible with one or more therapeutic, diagnostic, and/orenhancement agents, such as drugs, nutrients, microorganisms, in vivosensors, and tracers. In some embodiments, the active substance, is atherapeutic, nutraceutical, prophylactic or diagnostic agent. While muchof the specification describes the use of therapeutic agents, otheragents listed herein are also possible.

In a particular set of embodiments, the therapeutic agent is selectedfrom the group consisting of doxycycline hyclate, moxifloxacin,pyrazinamide, ethambutol, isoniazid, rifampicin, Streptomycin,moxifloxacin, interferon, peginterferon, ribavirin, paritaprevir,simepravir, grazoprevir, ladispavir, ombitasvir, elbasavir, daclatasvir,and sofosbuvir. Other therapeutic agents are also possible. For example,agents can include, but are not limited to, any synthetic ornaturally-occurring biologically active compound or composition ofmatter which, when administered to a subject (e.g., a human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. For example, usefulor potentially useful within the context of certain embodiments arecompounds or chemicals traditionally regarded as drugs, vaccines, andbiopharmaceuticals.

Certain such agents may include molecules such as proteins, peptides,hormones, nucleic acids, gene constructs, etc., for use in therapeutic,diagnostic, and/or enhancement areas, including, but not limited tomedical or veterinary treatment, prevention, diagnosis, and/ormitigation of disease or illness (e.g., HMG co-A reductase inhibitors(statins) like rosuvastatin, nonsteroidal anti-inflammatory drugs likemeloxicam, selective serotonin reuptake inhibitors like escitalopram,blood thinning agents like clopidogrel, steroids like prednisone,antipsychotics like aripiprazole and risperidone, analgesics likebuprenorphine, antagonists like naloxone, montelukast, and memantine,cardiac glycosides like digoxin, alpha blockers like tamsulosin,cholesterol absorption inhibitors like ezetimibe, metabolites likecolchicine, antihistamines like loratadine and cetirizine, opioids likeloperamide, proton-pump inhibitors like omeprazole, anti(retro)viralagents like entecavir, dolutegravir, rilpivirine, and cabotegravir,antibiotics like doxycycline, ciprofloxacin, and azithromycin,anti-malarial agents, and synthroid/levothyroxine); substance abusetreatment (e.g., methadone and varenicline); family planning (e.g.,hormonal contraception); performance enhancement (e.g., stimulants likecaffeine); and nutrition and supplements (e.g., protein, folic acid,calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, andother vitamin or mineral supplements).

In certain embodiments, the active substance is one or more specifictherapeutic agents. As used herein, the term “therapeutic agent” or alsoreferred to as a “drug” refers to an agent that is administered to asubject to treat a disease, disorder, or other clinically recognizedcondition, or for prophylactic purposes, and has a clinicallysignificant effect on the body of the subject to treat and/or preventthe disease, disorder, or condition. Listings of examples of knowntherapeutic agents can be found, for example, in the United StatesPharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic andClinical Pharmacology, McGraw-Hill/Appleton & Lange; 8th edition (Sep.21, 2000); Physician's Desk Reference (Thomson Publishing), and/or TheMerck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed(2006) following its publication, Mark H. Beers and Robert Berkow(eds.), Merck Publishing Group, or, in the case of animals, The MerckVeterinary Manual, 9th ed., Kahn, C. A. (ed.), Merck Publishing Group,2005; and “Approved Drug Products with Therapeutic Equivalence andEvaluations,” published by the United States Food and DrugAdministration (F.D.A.) (the “Orange Book”). Examples of drugs approvedfor human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331through 361, and 440 through 460, incorporated herein by reference;drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500through 589, incorporated herein by reference. In certain embodiments,the therapeutic agent is a small molecule. Exemplary classes oftherapeutic agents include, but are not limited to, analgesics,anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants,antiepileptics, antipsychotic agents, neuroprotective agents,anti-proliferatives, such as anti-cancer agents, antihistamines,antimigraine drugs, hormones, prostaglandins, antimicrobials (includingantibiotics, antifungals, antivirals, antiparasitics), antimuscarinics,anxioltyics, bacteriostatics, immunosuppressant agents, sedatives,hypnotics, antipsychotics, bronchodilators, anti-asthma drugs,cardiovascular drugs, anesthetics, anti-coagulants, inhibitors of anenzyme, steroidal agents, steroidal or non-steroidal anti-inflammatoryagents, corticosteroids, dopaminergics, electrolytes, gastro-intestinaldrugs, muscle relaxants, nutritional agents, vitamins,parasympathomimetics, stimulants, anorectics and anti-narcoleptics.Nutraceuticals can also be incorporated into the drug delivery article.These may be vitamins, supplements such as calcium or biotin, or naturalingredients such as plant extracts or phytohormones.

In another embodiment, the therapeutic agent is an immunosuppressiveagent. Exemplary immunosuppressive agents include glucocorticoids,cytostatics (such as alkylating agents, antimetabolites, and cytotoxicantibodies), antibodies (such as those directed against T-cell receptorsor II-2 receptors), drugs acting on immunophilins (such as cyclosporine,tacrolimus, and sirolimus) and other drugs (such as interferons,opioids, TNF binding proteins, mycophenolate, and other small moleculessuch as fingolimod).

In some embodiments, the therapeutic agent is a small molecule drughaving molecular weight less than about 2500 Daltons, less than about2000 Daltons, less than about 1500 Daltons, less than about 1000Daltons, less than about 750 Daltons, less than about 500 Daltons, lessor than about 400 Daltons. In some cases, the therapeutic agent is asmall molecule drug having molecular weight between 200 Daltons and 400Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltonsand 2500 Daltons.

In certain embodiments, the therapeutic agent is present in the articlein an amount greater than or equal to 1 gram, greater than or equal to 2grams, greater than or equal to 3 grams, greater than or equal to 5grams, greater than or equal to 10 grams, greater than or equal to 20grams, greater than or equal to 30 grams, greater than or equal to 40grams, greater than or equal to 50 grams, greater than or equal to 60grams, greater than or equal to 70 grams, or greater than or equal to 80grams, greater than or equal to 90 grams. In some embodiments, thetherapeutic agent is present in the article in an amount of less than orequal to 100 grams, less than or equal to 90 grams, less than or equalto 80 grams, less than or equal to 70 grams, less than or equal to 60grams, less than or equal to 50 grams, less than or equal to 40 grams,less than or equal to 30 grams, less than or equal to 20 grams, lessthan or equal to 10 grams, less than or equal to 5 grams, less than orequal to 3 grams, or less than or equal to 2 grams. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 1 gram and less than or equal to 100 grams, greater than or equal to2 grams and less than or equal to 100 grams, greater than or equal to 3grams and less than or equal to 100 grams). Other ranges are alsopossible.

In some embodiments, the articles described herein comprises two or moretypes of therapeutic agents. For example, in some embodiments, a firsttherapeutic agent and a second therapeutic agent are present in thearticle such that the total amount of the first and second therapeuticagent is in one or more ranges described above (e.g., the total amountof therapeutic agent is greater than or equal to 1 gram and less than orequal to 100 grams). In some embodiments, each therapeutic agent ispresent in an amount such that the total amount of therapeutic agents isgreater than or equal to 1 gram. In some embodiments, each therapeuticagent is present in an amount as described above (e.g., each therapeuticagent is present in an amount of greater than or equal to 1 gram andless than or equal to 100 grams).

In certain embodiments, the therapeutic agent is present in the articleat a concentration such that, upon release from the article, thetherapeutic agent elicits a therapeutic response.

In some embodiments, a subject may demonstrate health benefits, e.g.,upon administration of the article.

In some embodiments, the article comprises a polymer matrix (e.g.,polymeric material) having a reconfigurable shape. For example, in someembodiments, the article has a first shape/configuration (e.g., anelongated (e.g., straight) shape) and, upon removal of an elastic wire,obtains a second shape/configuration (e.g., a coil), different than thefirst shape.

The polymer matrix may be reconfigured, in some cases, into a shape suchas a straight shape, a J-hook shape, a spherical shape, a cylindricalshape, a coil shape, or a toroidal shape. Other shapes are alsopossible. In some embodiments, the polymeric material is reconfiguredupon insertion or removal of an elastic wire (e.g., from a hollow coreof the polymer matrix). In some embodiments, the reconfigured shape issuch that the article may be retained (e.g., at a location internal to asubject) as described in more detail herein. In some embodiments, thereconfigured shape has dimension incompatible with passage throughproximal and/or distal orifices of a containing viscus of a subject(e.g., such that the article is retained).

In some embodiments, the article has a maximum dimension (e.g., lengthwhen elongated) of greater than or equal to 20 cm, greater than or equalto 28 cm, greater than or equal to 30 cm, greater than or equal to 50cm, greater than or equal to 100 cm, greater than or equal to 200 cm, orgreater than or equal to 500 cm. In certain embodiments, the article hasa maximum dimension of less than or equal to 1000 cm, less than or equalto 500 cm, less than or equal to 200 cm, less than or equal to 100 cm,less than or equal to 50 cm, less than or equal to 30 cm, or less thanor equal to 28 cm. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to 20 cm and less than or equal to1000 cm, greater than or equal to 20 cm and less than or equal to 200cm). Other ranges are also possible.

In some embodiments, the shape of the polymeric material is configuredto be reconfigured such that the article has a maximum overall diameter(e.g., in the second configuration) of greater than or equal to 2 cm,greater than or equal to 5 cm, greater than or equal to 10 cm, orgreater than or equal to 25 cm. In certain embodiments, the shape of thepolymeric material is configured to be reconfigured such that thearticle has a maximum overall diameter of less than or equal to 50 cm,less than or equal to 25 cm, less than or equal to 10 cm, or less thanor equal to 5 cm. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to 2 cm and less than or equal to50 cm, greater than or equal to 10 cm and less than or equal to 25 cm).Other ranges are also possible.

In some embodiments, the article has a size and/or configuration suchthat the article does not fit inside a standard capsule (e.g., a capsulehaving a shape or size as described in the USP including, but notlimited to, 000 capsule, 00 capsule, 0 capsule, 1 capsule, 2 capsule, 3capsule, 4 capsule, or 5 capsule). That is to say, in some embodiments,the article is not configured to be delivered in a capsule. As describedherein, in some embodiments, the article is configured to beadministered transesophageally.

In certain embodiments, the article is configured to be retained at alocation internal to a subject for a relatively long period of time. Forexample, in some embodiments, the article is retained at the locationinternal to the subject for at least about 1 day, at least about 3 days,at least about 7 days, at least about 2 weeks, at least about 1 month,at least about 2 months, at least about 6 months, at least about 1 year,or at least about 2 years. In certain embodiments, the article isretained at the location internal to the subject for less than or equalto about 3 years, less than or equal to about 2 years, less than orequal to about 1 year, less than or equal to about 1 month, less than orequal to about 1 week, or less than or equal to about 3 days.Combinations of the above-referenced ranged are also possible (e.g.,between about 24 hours and about 3 years, between about 1 week and 1year, between about 1 year and 3 years). Other ranges are also possible.

In some embodiments, the article may be designed and configured to havea relatively low force of administration (e.g., the force required toadminister the device through a nasogastric or endoscopic tube). Incertain embodiments, the article has an administration force of lessthan or equal to 20 N, less than or equal to 10 N, less than or equal to5 N, or less than or equal to 1 N. In some embodiments, the article hasan administration force of greater than or equal to 0.1 N, greater thanor equal to 1 N, greater than or equal to 5 N, or greater than or equalto 10 N. Combinations of the above-referenced ranges are also possible(e.g., greater than or equal to 0.1 N and less than or equal to 20 N).Other ranges are also possible.

In some embodiments, the polymeric material may be encapsulated (e.g.,by an elastomeric hollow tube)

In some embodiments, the location internally of the subject is thecolon, the duodenum, the ileum, the jejunum, the stomach, or theesophagus.

Retrieval systems and related methods (e.g., for gastric residentarticles) are also provided. In some embodiments, the retrieval systemis configured to be administered transesophageally to a locationinternal to a subject such that a gastric residence system (e.g., one ormore articles and/or components described herein), located at thelocation internal to the subject, may be retrieved (e.g., removed fromthe subject). Advantageously, the systems described herein may be smallenough to be fit through the esophagus of a subject to non-invasivelyaccess the stomach and/or may be operated without the use of endoscopyand/or imaging (e.g., x-ray imaging). In some cases, the systemsdescribed herein may be configured to sense (e.g., via a sensorassociated with the system) one or more gastric resident devices presentin the subject. In some embodiments, upon detection of the gastricresident system, the retrieval system outputs a contact signal (e.g.,via the sensor) such that a user may retrieve the device. In certainembodiments, the system may be configured to contact and bind with thegastric resident system (e.g., while able to hold the weight of thegastric resident system and retrieve it through the esophagus of thesubject).

In some embodiments, the system comprises a polymeric component having aflexible member and a binding component associated with an end portionof the polymeric component. In some embodiment, the polymeric componentcomprises a flexible tube.

In some embodiments, the system may be administered transesophageally toa subject. In certain embodiments, the system comprises a sensorassociated with an end portion of the polymeric component. In somecases, the sensor may be used to determine a distance between thebinding component and the gastric residence system present at thelocation internal to the subject. The sensor may be, in some cases,adjacent (e.g., directly adjacent) an end portion of the polymericcomponent.

In some embodiments, upon administration of the retrieval system to thelocation internal to the subject, the retrieval system may interface,via a locking mechanism associated with an end portion of the polymericcomponent, with the gastric residence system. The locking mechanism maybe, in some cases, adjacent (e.g., directly adjacent) an end portion ofthe polymeric component. In certain embodiments, after interfacing withthe gastric residence system, the gastric residence system may beremoved (e.g., via the retrieval system) from the location internal tothe subject. In some embodiments, the system is configured to maintaincontact (e.g., via the binding mechanism, via the locking mechanism)with the gastric residence system during extraction of said gastricresidence system from a location internal to a subject.

In certain embodiments, the binding component comprises a magnet. Insome such embodiments, the system is configured to magneticallyassociate (e.g., bind) with a gastric residence system.

In some embodiments, the binding component comprises a first speciesconfigured to interact with a second species via a binding event.

In some embodiments, the first species of the binding componentinteracts with a second species via formation of a bond, such as anionic bond, a covalent bond, a hydrogen bond, Van der Waalsinteractions, and the like. The covalent bond may be, for example,carbon-carbon, carbon-oxygen, oxygen-silicon, sulfur-sulfur,phosphorus-nitrogen, carbon-nitrogen, metal-oxygen, or other covalentbonds. The hydrogen bond may be, for example, between hydroxyl, amine,carboxyl, thiol, and/or similar functional groups. For example, thespecies may include a functional group, such as a thiol, aldehyde,ester, carboxylic acid, hydroxyl, and the like, wherein the functionalgroup forms a bond with the nanodiamond particle. In some cases, thespecies may be an electron-rich or electron-poor moiety whereininteraction between the first species and the second species comprisesan electrostatic interaction.

In some cases, the first species of the binding component may comprise abiological or a chemical group capable of binding another biological orchemical molecule. For example, the first species may include afunctional group, such as a thiol, aldehyde, ester, carboxylic acid,hydroxyl, and the like, wherein the functional group forms a bond withthe second species.

In some embodiments, the first species and the second species interactvia a binding event between pairs of biological molecules includingproteins, nucleic acids, glycoproteins, carbohydrates, hormones, and thelike. Specific examples include an antibody/peptide pair, anantibody/antigen pair, an antibody fragment/antigen pair, anantibody/antigen fragment pair, an antibody fragment/antigen fragmentpair, an antibody/hapten pair, an enzyme/substrate pair, anenzyme/inhibitor pair, an enzyme/cofactor pair, a protein/substratepair, a nucleic acid/nucleic acid pair, a protein/nucleic acid pair, apeptide/peptide pair, a protein/protein pair, a small molecule/proteinpair, a glutathione/GST pair, an anti-GFP/GFP fusion protein pair, aMyc/Max pair, a maltose/maltose binding protein pair, acarbohydrate/protein pair, a carbohydrate derivative/protein pair, ametal binding tag/metal/chelate, a peptide tag/metal ion-metal chelatepair, a peptide/NTA pair, a lectin/carbohydrate pair, a receptor/hormonepair, a receptor/effector pair, a complementary nucleic acid/nucleicacid pair, a ligand/cell surface receptor pair, a virus/ligand pair, aProtein A/antibody pair, a Protein G/antibody pair, a Protein L/antibodypair, an Fc receptor/antibody pair, a biotin/avidin pair, abiotin/streptavidin pair, a drug/target pair, a zinc finger/nucleic acidpair, a small molecule/peptide pair, a small molecule/protein pair, asmall molecule/target pair, a carbohydrate/protein pair such asmaltose/MBP (maltose binding protein), a small molecule/target pair, ora metal ion/chelating agent pair. Specific non-limiting examples ofspecies include peptides, proteins, DNA, RNA, PNA. Other species andbinding pairs are also possible.

In some embodiments, the sensor is configured to determine a distancebetween the binding component and the gastric residence system. Forexample, the sensor may be configured to determine, in some cases, thedistance between a magnetic component associated with the retrievalsystem and a magnet associated with the gastric residence system. In aparticular set of embodiments, the sensor is a Hall effect sensor. Othersensors are also possible.

As described above and herein, in some embodiments, the system comprisesa locking mechanism (e.g., for anchoring the gastric residence system tothe retrieval system). In certain embodiments, the locking mechanismcomprises a snare. In some embodiments, the locking mechanism comprisesa plurality of barbed features (e.g., barbs).

In some embodiments, the system is configured to pass through anasogastric and/or endoscopic tube. For example, in certain embodiments,the system has a maximum diameter less than or equal to 7 mm, less thanor equal to 6.5 mm, less than or equal to 6 mm, less than or equal to 5mm, less than or equal to 4 mm, less than or equal to 3 mm, or less thanor equal to 2.5 mm. In some embodiments, the system has a maximumdiameter of greater than or equal to 2 mm, greater than or equal to 2.5mm, greater than or equal to 3 mm, greater than or equal to 4 mm,greater than or equal to 5 mm, greater than or equal to 6 mm, or greaterthan or equal to 6.5 mm. Combinations of the above-referenced ranges arealso possible (e.g., less than or equal to 7 mm and greater than orequal to 2 mm). Other ranges are also possible.

In some embodiments, the gastric residence systems described herein maycomprise one or more features and/or articles described in a co-ownedU.S. Provisional Patent Application Ser. No. 62/678,471, filed May 31,2018, and entitled “RESIDENT ARTICLES FOR GRAM-LEVEL DOSING,” and/or ina co-owned U.S. Provisional Patent Application Ser. No. 62/678,492,filed May 31, 2018, and entitled “DRUG DELIVERY ARTICLES FOR GRAM-LEVELDOSING,” and/or in a co-owned U.S. Provisional Patent Application Ser.No. 62/817,477, filed Mar. 12, 2019, and entitled “DRUG DELIVERYARTICLES FOR GRAM-LEVEL DOSING,” each of which is incorporated herein byreference in its entirety.

In some embodiments, the location internally of the subject is thecolon, the duodenum, the ileum, the jejunum, the stomach, or theesophagus.

EXAMPLES

The following examples are intended to illustrate certain embodimentsdescribed herein, including certain aspects of the present invention,but do not exemplify the full scope of the invention.

The following examples, in some or all of the examples, demonstrate drugdelivery formulations combined with a gastric resident article capableof e.g., one-time administration through a nasogastric or endoscopictube, safe retention in the gastric cavity, 2 weeks of drug release,and/or one-time transesophageal retrieval through a nasogastric orendoscopic tube. The drug delivery formulations may have featuresincluding, for example, 1) attachment to a superelastic wire, 2)homogenous dispersion of the drug, 3) made of biocompatible components,4) maintain stability of the drug form once formulated, and/or 5) havean outer diameter less than 20 French (6.667 mm) in diameter to fitwithin a nasogastric tube.

The following examples, in some or all of the examples, demonstratearticles capable of one-time administration and retrieval, extendedresidence, and/or release of pharmacologically active therapies forweeks to months with a holding capacity of more than 10 grams of activepharmaceutical ingredient (API). Gastric retention in vivo with durableresidence times has been demonstrated. High levels of drug loading andstability were achieved. Such article could serve as a platform tomaximize adherence to a broad range of drugs.

In some examples, the article consisted of a series of shapes with thecapacity for holding at least 10 grams of API and therefore at least28.66 cm in length but also compatible with one-time transesophagealadministration, effective gastric retention, and one-timetransesophageal retrieval. The devices can be, in some cases, deliveredand retrieved via a nasogastric or endoscopic tube, which is insertedinto the stomach by the nose and is advantageous to use for one-timeadministration and retrieval of the device.

The article may be small enough to be fit through the esophagus of apatient to non-invasively access the stomach, able to adopt a shape inthe gastric cavity large enough to prevent passage through the pylorus,comprise high levels of drug loading, and/or include controlled drugrelease with no potential for burst release. In some examples, the drugis stable in the hostile gastric environment for extended duration. Thearticle may be capable of degrading into forms which have no potentialfor intestinal obstruction and which can readily pass or be retrievedonce the drug has been released from the device.

The following examples, in some or all of the examples, describearticles having shapes that are safe transesophageal administration,safe for retention in the gastric cavity, are capable of holding greaterthan or more than 10 grams of API, and/or are safe transesophagealretrieval.

The following examples, in some or all of the examples, demonstrate aretrieval system capable of safely being administered through anasogastric or endoscopic tube, sensing a gastric resident drug deliverydevice, and/or retrieving it via a nasogastric or endoscopic tube. Insome cases, the retrieval system has one or more of the followingcomponents: 1) a Hall effect sensor for detection of the gastricresident device, 2) an output of the Hall effect sensor, and 3) a magnetto contact the gastric resident system and facilitate retrieval. Thesensor is incorporated, for example, to provide distance-correlatedanalog sensing of the magnetic field output by magnets in the gastricresident system. The three pins of the sensor may be soldered to wiresthat are then connected to a breadboard for power and display of thedistance to the magnets. The entire system is designed to ensure safepassage through the nasogastric tube (e.g., an outer diameter of thesystem is less than 20 French (6.667 mm) in diameter and at least 2 feetin length to reach the stomach.)

In some examples, the system includes one or more of the followingfeatures: 1) such a system may be small enough to be fit through theesophagus of a patient to non-invasively access the stomach; 2) such asystem may sense the gastric resident system without using endoscopy orimaging; 3) upon detection of the gastric resident system's magnet, theretrieval system may output a contact signal to the user retrieving thesystem; and 4) the system may make contact with the gastric residentsystem while able to hold the weight of the gastric resident system andretrieve it through the esophagus of the patient.

Example 1

Cylindrical pills of drug were mixed with vinylpolysiloxane with heightgreater than 5 mm and diameter of 4 mm They had a hollow core (e.g.,hole) with diameter 0.5 mm in the middle to allow a superelastic wire tofit inside. The model drug, doxycycline hyclate, is added to theZhermack Elite Double 22 base and catalyst to obtain a final drugloading percentage of 32%. Each pill has around 30 mg of drug (FIG. 1B).Drug crystals less than 75 μm can be visualized on the surface of thepill using scanning electron microscope (FIG. 1C). A series of pillswith 0.5 mm holes inside them can be strung on a retention frame such asnitinol superelastic wire and encased in a Tygon tubing with stainlesssteel beads and Nusil glue at the ends of the article (FIG. 1D). Otherdrugs such as moxifloxacin, isoniazid, pyrazinamide, and ethambutol canalso be mixed with the Zhermack Elite Double 22 base and catalyst atdrug loading percentages greater than 25 wt %. Stability of the drugform can be evaluated using proton nuclear magnetic resonancespectroscopy after extraction of the drug from the matrix in water.

The pills were created by first mixing the drug into the Zhermack EliteDouble 22 base and catalyst. Other excipient polymers, such aspolyethylene glycol, were also added in desired amounts as powders totune the drug release. Drug loading percentages were determined relativeto the finally cured silicone mixture weight. The silicone, drug, andexcipient mixture were mixed at 1800 rpm for 30 seconds using theSpeedMixer™ DAC 150.1 FVX-K from Hauschild, Germany. The viscous uniformblend was poured into a polystyrene Petri dish, and individual pillswere extracted using a 4 mm Miltex disposable biopsy punch (FIG. 2A). Acustom fixture with 25 Gauge needles was used to core out a 0.5 mm holein a series of 50 pills (FIG. 2B). The nitinol wire was inserted intothe holes of the pills, and the ends of the nitinol wire were engulfedin 0.024 inch diameter heat-shrink tubing and inserted into a 2 inchpiece of Tygon tubing (I.D.×O.D. 3/16×0.25 in.). The end of the tubingwas filled with Med3-4213 silicon adhesive from Nusil followed by a ¼inch stainless steel ball bearing pressed in. More silicone adhesive wasfilled behind the ball bearing to completely seal the tubing and lock inthe nitinol (FIG. 2C).

Flexible tubing can be surrounding all the pills with biopsy-punched ordrilled holes in the tubing to allow stomach acid to reach thedrug/siloxane pills. The ends of the nitinol wire may be sealed usingglue or molten polymers such as Ellastolan or polycaprolactone.

Excipients can be added to the drug/siloxane matrix to tune the rate ofrelease. For example, polyethylene glycol (PEG) 3350 can be added toincrease the rate of release (FIG. 3A). Other molecular weights of PEGcan also enable the same trend of increasing the release rate as morePEG is added.

The choice of matrix polymer can be vinylpolysiloxane, like the ZhermackElite Double 22 base and catalyst, or it can be other polymers such aspolydimethylsiloxane, polycaprolactone, polyethylene, orpolyethylene-vinyl acetate. One article can have a combination of avariety of matrix system formulations with different excipients to tunethe rate of drug release.

After deployment of the drug delivery formulations in three Yorkshirepigs in a large animal model, concentrations of doxycycline hyclate inthe blood were measured, and drug release is sustained for at least 7days with non-zero values (FIG. 3B).

Example 2

Coated cylindrical pills (articles) comprising drug and mixed withvinylpolysiloxane with height between 3-4 mm and diameter of 4 mm Theyhad with a hole with diameter 0.5 mm in the middle to allow asuperelastic wire to fit inside. The model drug, doxycycline hyclate,was added to the Zhermack Elite Double 22 base and catalyst to obtain afinal drug loading percentage of 32%. The uncoated pill is shown on theleft in FIG. 4A, and the coated pill is shown on the right in FIG. 4B.The coatings help, for example, to prevent the burst release of drugfrom the surface of the pill. A library of coatings has been applied tothe pills using a E91 airbursh and conventional pan coater attached to aEwreka 403 unit: Eudragit RS PO, Eudragit NM 30D, polycaprolactone,ethylcellulose, cellulose acetate, cellulose acetate butyrate (CAB),polydimethysiloxane (PDMS), and vinylpolysiloxane (VPS).

A series of coated pills with 0.5 mm holes inside them can be strung ona retention frame such as nitinol superelastic wire and encased in aTygon tubing with stainless steel beads and Nusil glue at the ends ofthe article (FIG. 1D). Other drugs such as moxifloxacin, isoniazid,pyrazinamide, and ethambutol can also be mixed with the Zhermack EliteDouble 22 base and catalyst at drug loading percentages greater than 25wt %. Pills of those drugs can also be coated using a conventional pancoater and airbrush.

The pills were created following the same procedure in Example 1. Thecoating solutions are dyed with red food coloring powder or iron oxideto visualize them around the green doxycycline hyclate/siloxane matrix.FIG. 4B shows a 149 μm Eudragit NM 30D coating, and FIG. 4C shows a 174μm Eudragit RS PO coating. Other coatings, such as cellulose acetatebutyrate, cellulose acetate, and PDMS have been described and developedelsewhere.

Articles with a series of 30 pills were made so that there was 1 gram ofdoxycycline hyclate in 2 grams of vinylpolysiloxane. Pills were coatedwith either cellulose acetate butyrate (CAB) or with Eudragit RS PO. Acontrol with no coatings was also made. The articles were immersed insimulated gastric fluid, and the cumulative release of doxycyclinehyclate was measured for more than 26 days. The articles with coatings,CAB and Eudragit RS PO, prevented the burst release in the first coupledays (FIG. 4D). Drug release was achieved for more than 26 days.

PEG 3350 was added to the matrix, and the effect of coatings Eudragit RSPO and Eudragit NM 30D coatings is shown in FIG. 5A. The coated pillsprevented the burst release in the first day, and then the thickercoating of Eudragit NM 30D had a slower rate of release. Thickness ofcoatings was tuned by increasing the spray volume. PDMS with differentviscosities (750 cst and 25 cst) were applied as a coating to the pillsand also blunted the burst release and slowed down the release rate(FIG. 5B).

Example 3

In another implementation shown in FIG. 6, a multi-matrix pill can bemade with different layers of drug/matrix concentrations. Themulti-matrix pill has a series of concentric cylinders with theoutermost cylinder having a diameter of 4 mm and height of more than 5mm. To prevent the burst release, the outer layer of the pill can have alow concentration of drug relative to the matrix material. The nextlayer moving inwards can have a higher concentration of drug relative tothe matrix. Then, there must be a 0.5 mm hole for the retention framesuperelastic wire like nitinol to pass. The multi-matrix pill could havemany such layers with a gradient of drug concentrations starting withlow to high from the outer surface of the pill to the inside. FIG. 4Dshows the multi-matrix pill reducing the burst release and release rateof doxycycline hyclate. The multi-matrix pills can also be coatedfurther using the coating described in Example 2.

Example 4

FIG. 7 shows another drug delivery system made of pills made of hollowtubing sealed with adhesive on the ends. Outer diameter of tubing is ¼inch, and the inner diameter is 3/16 inch. The length of the tubing ismore than 5 mm and it has drug powder in it. Drug release can occur bydiffusion through micro-drilled or laser-cut holes in the tubing. Theseholes can be coated with polymer films that degrade at different timesor are porous to control the rate of drug release. The nitinol wire canpass through the packed drug powder and connect multiple series of thesepills.

Example 5 Design of a Gastric Residence System (GRS) for MultigramDosing

A large-dose GRS for long-term treatment, in some embodiments, isdesigned to (i) have a size and shape that can fit through the esophagusof a patient to non-surgically access the stomach, (ii) have the abilityto adopt an alternative con-formation in the stomach that preventspassage through the pylorus, (iii) achieve high concentrations of drugloading, (iv) be composed of biocompatible materials that are stable foran extended duration in the acidic gastric environment, (v) have nopotential for gastrointestinal obstruction or perforation, and/or (vi)either be able to degrade into forms that can safely pass or beretrieved after the drug has been released from the device. Here, a GRSwas designed that could be administered through an NG tube, which isinserted via the nose to access the stomach. After reaching the stomach,the GRS forms a cylindrical coil and continually releases grams of drugover the course of weeks, whereupon the device is retrieved back throughan NG tube (FIG. 8A). The assembled GRS consisted of a superelasticnitinol wire as the retention frame upon which drug pills are strungwith a retainer and tubing at the ends of the device (FIG. 8B). Totailor the drug loading and duration of therapy, the length of the GRSand formulation of drug pills may be modified (FIGS. 11A-11D).

A coiled nitinol wire inside tubing was deployed to the gastric cavityof 30- to 75-kg Yorkshire pigs to demonstrate transesophagealadministration and safe gastric retention in vivo. Yorkshire pigsgenerally have similar gastric anatomy to humans and have beenpreviously used to evaluate long-acting drug delivery platforms.Representative serial abdominal radiographs during device deployment andmonth-long residence revealed the feasibility of the GRS to pass throughthe esophagus and form a coil in the stomach within 50 s (FIG. 8C).Without wishing to be bound by theory, the GRS was able to curl backinto its original coil shape in the gastric cavity after passing throughthe esophagus because of, for example, the superelasticity of nitinol.Safe long-term gastric residence was evaluated by serial radiographsobtained over the course of 1 month and through endoscopic evaluation(FIG. 8C and FIG. 12). Even after prolonged gastric residence of theselarge devices, mucosal surfaces of the animals' stomachs did not showinjury, erosions, or ulcerations; in addition, the animals did not showany weight loss, evidence of GI obstruction, or limitation in thepassage of food or liquid (FIGS. 13A-13C).

The GRS was designed to be retrieved through an NG tube after therelease of the drug payload in the gastric cavity. The retrieval deviceconsisted of a Hall effect sensor to determine the distance between amagnet on the end of the GRS and a magnet at the end of retrieval device(FIG. 8D). To ensure the stability of the Hall effect sensor in a low pHenvironment, it was placed in simulated gastric fluid (SGF) for 90 min;the measured voltage was comparable to the voltage measured in airbefore immersion in SGF (FIG. 14A). A three-dimensional (3D) printed invitro human stomach model was constructed to test the feasibility of theretrieval procedure (FIG. 14B). A magnet was placed on each end of theGRS to maximize likelihood of retrieval. In vivo demonstration of GRSretrieval was successful, as demonstrated by representative serialradiographs (FIG. 8D). Thus, the potential of the GRS to be safelyadministered, to reside safely in the gastric cavity for 1 month, and tobe retrieved through the esophagus, was demonstrated.

Controlled Drug Release With Coated Drug-Matrix Pills

Pills of a single drug mixed were fabricated inside a silicone matrixand encapsulated each pill in a polymer coating to enable tailoreddosing of each drug (FIG. 9A). Vinylpolysiloxane (VPS) was selected as adrug release matrix because of its flexibility, rapid curing time, andlow-temperature mixing process with drug. A 300-μm-thick Eudragit RS 100polymer coating was spray coated to help prevent the burst release ofdrug from the surface of the matrix. Each pill had a height and diameterof 4 mm with a 0.5-mm hole in the center through which to pass thenitinol wire and contribute to the assembled GRS (FIG. 9A).

Drug-VPS pills were assembled for multiple antibiotics used for TBtreatment including doxycycline hyclate, isoniazid, ethambutol,pyrazinamide, moxifloxacin, and rifampicin. As demonstrated withdoxycycline hyclate, the drug release rate from the VPS matrix in SGFmay be tuned by varying the amount of a hydrophilic polymer,poly(ethylene glycol) (PEG), mixed within the VPS (FIG. 9B). The PEGdomains acted as channels inside the hydrophobic VPS matrix that candissolve and form pores for the doxycycline hyclate to release.Furthermore, formulations that were coated with Eudragit RS 100 showed alinear kinetic profile with limited burst release of doxycycline hyclate(FIG. 9B). The drug-VPS pills were also able to release isoniazid,ethambutol, pyrazinamide, moxifloxacin, and rifampicin in vitro,indicating that the VPS matrix is compatible with a wide variety of TBdrugs (FIGS. 9C-G).

In Vivo Sustained Delivery of Antibiotic for 4 Weeks

Having demonstrated controlled release with coated drug-matrix pills invitro for 1 month, GRSs were loaded with 10 g of doxycycline hyclate asa model drug (FIG. 10A) and administered in swine. The GRS was assembledto contain 600 pills using four different formulations—two each withEudragit RS 100 or PCL coatings—which released drug simultaneously(FIGS. 15A-15B). After 28 days of gastric residence in vivo, the GRS wassafely retrieved (FIG. 10B). The serum concentration profile of a 100-mgsingle dose is shown in FIG. 10C. The drug was absorbed rapidly, anddetectable concentrations were observed within 15 min. No drug wasdetectable after 3 days with the single-dose formulation. In contrast,drug was detectable for at least 28 days when doxycycline hyclate wasdosed in the GRS. Rifampicin was also incorporated into the GRS andachieved detectable serum concentrations for a week in vivo (FIG. 16).

Preliminary End-User Assessment and Economic Impact of the GRS

111 TB health care providers and 300 patients were surveyed and learnedthat a long-term drug delivery device administered through an NG tubewas acceptable and feasible in the field (FIGS. 17A-17F and 18A-18C). Anestablished model was used to evaluate the potential impact of a GRS onpatients with TB, with savings estimated at more than $8000 per patient.

General Discussion

A GRS capable of multigram-level dosing of a TB antibiotic over thecourse of 4 weeks was developed. The GRS drug pills were generallycompatible with all first-line TB antibiotics, and it was anticipatedthat further formulation development and large-scale manufacturing withan array of polymer matrices and coatings will optimize a linear drugrelease profile in the gastric cavity to reduce variability in serumconcentrations and match drug release kinetics across drugs. Thesemacrodevices showed no evidence of GI obstruction or injury duringgastric residence and retrieval, as supported by radiographic,endoscopic, and histopathologic evaluation in a swine model.

Adherence to TB treatment is generally challenging because of the longand frequent dosing regimen, and additional patient-centeredinterventions may be necessary to supplement directly observed therapyshort course (DOTS) in resource-constrained environments. Technologiessuch as the GRS described here can improve the effectiveness of DOTS byensuring that patients receive their medication over the course ofextended periods of time, thereby reducing the frequency of clinicvisits. Less frequent dosing visits would reduce the potential impact ondaily life, specifically on productivity of individuals receivingtreatment for TB. The ability of the GRS to contain and serve as amultigram drug depot in the gastric cavity supports further developmentof prolonged drug depots on the order of weeks and even months, whichcould mitigate the effects of poor adherence.

To establish a route for translation, it was anticipated that the fulldevelopment of these devices will include preclinical evaluation in anadditional animal model such as the dog. Optimizing drug releasekinetics is a critical next step, such that serum concentrations of thedrug remain within the therapeutic window and do not generally increasethe likelihood of drug resistance. Different diet conditions may betested to understand the effect on pharmacokinetic parameters across abroad spectrum of drugs.

In addition, the importance of amplifying training of health careworkers to deploy NG tubes safely was recognized, so that the GRS can beimplemented alongside DOTS interventions in the field where trainedpersonnel are generally present. Because patients will be consciousduring the NG tube procedure, they will be able to speak to a healthcare worker to ensure correct placement of the tube.

To begin addressing the acceptability and feasibility of the NG tubeapproach, a preliminary field questionnaire of 300 patients with TB and111 TB health care workers in TB clinics. Survey results indicated thatmore than 90% of health care personnel have experience deploying NGtubes, and patients prefer the use of an NG tube for deployment of amonth-long TB treatment as opposed to swallowing many capsules ordrinking liters of water-drug mixture as potential alternative modes ofgenerating large drug depots. It was further demonstrated that thepotential impact of the implementation of our GRS to improve adherencein terms of lives saved and economic savings for patients suffering fromTB.

Macrodevices consisting of multigram drug depots could have an impactacross a range of diseases in addition to TB and could be coupled toother procedures such as endoscopy. For broad implementation, a range ofchemical therapeutics may be incorporated into the modular pill designof the GRS. Formulations may be optimized to ensure high drug loadingefficiencies and controlled release profiles for efficacious treatmentand controlled drug release. The GRS has potential as a platformtechnology for improving medication adherence and thereby also improveoutcomes for patients suffering from a myriad of diseases.

Materials and Methods Study Design

Devices for month-long drug delivery in the gastric cavity weredesigned, fabricated, and tested. In some embodiments, the GRS containsa series of drug pills loaded onto a nitinol shape memory alloy wire.The device may form a coil shape after reaching the stomach. A retrievaldevice compatible with nasogastric administration may use a sensor andmagnet to attach to a magnet on the GRS. Radiographic, endoscopic, andhistopathologic evaluation were conducted.

End-user acceptability and feasibility of NG tube placement was assessedthrough a questionnaire of 111 TB health care providers and 300 patientswith TB at DOTS clinics. Sample sizes were determined on the basis of aconservative method with a 90% confidence interval and 8% margin oferror for the health care providers and 90% confidence interval and 5%margin of error for the patients. All health care providers who filledout more than 90% of the questionnaire were included in the analysis.All 300 patients who provided consent for the study were included in theanalysis. An economic model was applied to quantify the impact of theGRS.

Manufacturing of the Gastric Resident System (GRS)

The assembled GRS consisted of a superelastic nitinol wire as theretention frame upon which drug pills are strung with a retainer andtubing at the ends of the device. Nitinol wire, with diameter of 0.59 mmand phase transformation at 37° C., was wrapped around a custom fixtureto create a helical shape and secured in place using steel screws. Thenitinol-fixture assembly was placed in a furnace at 500° C. for 15minutes and then quenched in water at room temperature for 20 minutes.The nitinol was unwrapped from the fixture, ready for pills to be added.

Doxycycline hyclate was purchased from MedChem Express LLC. Isoniazidwas purchased from Sigma-Aldrich Corporation, and moxifloxacin waspurchased from ArkPharm, Inc. Rifampicin, ethambutol, and pyrazinamidewere purchased from Hangzhou Hysen Pharma Co. Ltd. Drug pills were madeusing the following protocol: The drug was first added to thevinylpolysiloxane (VPS) base (Zhermack Elite Double 22) and mixed at3200 rpm for 30 seconds using a SpeedMixer DAC 150.1 FVX-K (FlackTekInc.). To prevent drug loss, it was ensured that all the drug was mixedinto the matrix before proceeding. After 2 minutes of cooling,poly(ethylene glycol) (PEG) molecular weight 3500 (Sigma-AldrichCorporation) or molecular weight 400 (Sigma-Aldrich Corporation) wasadded and mixed into the drug-VPS base matrix using the SpeedMixer at2700 rpm for 30 seconds. After 2 minutes of cooling, the VPS catalyst(Zhermack Elite Double 22) was added and mixed using the SpeedMixer at1750 rpm for 30 seconds. Drug loading percentages were determinedrelative to the final cured silicone mixture weight: doxycycline hyclate(32%), isoniazid (32%), ethambutol (25%), pyrazinamide (30%),moxifloxacin (20%), and rifampicin (54%). The viscous uniform blend waspoured into a disposable polystyrene Petri dish (VWR), and individualpills were extracted using a 4 mm Miltex disposable biopsy punch(Integra). A 0.5 mm biopsy punch (Electron Microscopy Sciences) was usedto core out a hole in the center of the drug-VPS pill to allow thenitinol wire to pass through.

The pills were spray-coated in a DKE stainless steel pan (ERWEKA GmbH)with a 9.5 L capacity attached to an AR 403 drive unit (ERWEKA GmbH).The Eudragit RS 100 (Evonik Corporation) solution was prepared asrecommended by Evonik (60). Briefly, the Eudragit RS 100 pellets weredissolved in 50% of a diluent mixture, composed of 342.90 grams ofacetone (Sigma-Aldrich Corporation), 514.20 grams of isopropanol(Sigma-Aldrich Corporation), and 42.90 grams of water. In a separatebeaker, an excipient mixture of talc (<10 μm particle size fromSigma-Aldrich Corporation), triethyl citrate (Sigma-AldrichCorporation), and red dextrose food dye (CK Products) was homogenizedinto the remaining 50% of the diluent mixture for 15 minutes. Theexcipient mixture was then poured into the beaker containing theEudragit solution and stirred. Lastly, the spray suspension was passedthrough a 500 μm sieve (McMaster-Carr). To prepare apoly(ε-caprolactone) (PCL) spray solution, PCL molecular weight 45,000(Sigma-Aldrich Corporation) was added to acetone at 5% weight pervolume. The solution was then placed on a hot plate with a stir bar at50° C. and 200 rpm. The PCL pellets started to fully dissolve and form ahomogenous solution after one hour. The spray gun used was a 0.8 mmnozzle, handheld Master E91 airbrush (TCP Global) attached to beakers inthe kit with a spray volume of 18 mL and held at a 90° angle to therotating pan with a 7 cm distance from its outer diameter. The coatingpan was tilted at a 45-degree angle for all the formulations and rotatedat 70 rpm for the Eudragit RS 100 solution and at 300 rpm for the PCLsolution. A heat gun (Uline) was placed directly underneath the coatingpan and set to 50° C. to induce film formation on the pills sprayed withEudragit RS 100. The Eudragit RS 100 sprayed pills were dried for 2hours after spraying in a circulating air oven set at 40° C. The typicalbatch size for spraying was 100 pills. It took 120 minutes to spraypills with 300 mL of Eudragit RS 100, and it took 100 minutes to spraypills with PCL.

The nitinol wire was inserted into the 0.5 mm hole of the coateddrug-VPS pills, and after the desired loading was achieved, each end ofthe nitinol wire was crimped using a pair of pliers. PCL molecularweight 37,000 (Sigma-Aldrich Corporation) pellets were then pressed intotwo 3-inch (76.2 mm) long pieces of Tygon tubing (Inner Diameter×OuterDiameter: 4.76×6.35 mm), which was obtained from McMaster-Carr. The endof each tube was then filled with Med3-4213 silicone adhesive (NuSil),followed by a 6.35 mm stainless steel ball bearing. Once completelypacked with the pellets, the tubes were heated at 100° C. to melt thePCL using a heat gun. Each crimped end of the nitinol was then slowlyinserted into the molten PCL and set into place as the PCL cooled atroom temperature to solidify around the nitinol wire. More siliconeadhesive was used to seal the free ends of the tubes at both ends of thedevice.

In Vivo Evaluation of the Immediate Release and Gastric Resident System(GRS)

To assess the oral pharmacokinetics of immediate release formulationsand gastric retentive drug delivery devices, they were administered to alarge animal model (30-75 kg Yorkshire pigs). This model was chosenbecause its gastric anatomy is similar to that of humans and is widelyused in evaluating devices in the GI tract. Animals were fed daily inthe morning and in the evening with a diet consisting of pellets(Laboratory mini-pig grower diet, 5081), in addition to a midday snackconsisting of various fruits and vegetables. The pellets consisted ofground oats, alfalfa meal, wheat middlings, soybean meal, dried beetpulp, salts, and other micronutrients.

The immediate release formulation was prepared by weighing and filling100 mg of doxycycline hyclate in a “00” gelatin capsule (Purecaps USA)15 minutes prior to dosing. Prior to dosing, the pigs were sedated withTelazol® (5 mg/kg IM), xylazine (2 mg/kg IM), and atropine (0.04 mg/kgIM), intubated, and maintained with isoflurane (1 to 3% inhaled).

Immediate release and GRS formulations were deployed in the stomach viaan endoscopic guided overtube (Inner Diameter×Outer Diameter: 16.7×19.5mm) from US Endoscopy. The overtube was removed once the devices wereadministered. For evaluation of the safety and residence time of thegastric retentive drug delivery devices, the animals were clinicallyassessed twice a day for evidence of GI obstruction includinginappetence, abdominal distension, lack of stool, and vomiting.Additionally, the animals were evaluated radiographically every day 3-4days for evidence of GI obstruction and/or perforation. Tissue sampleswere collected before and after the device was placed in the stomach forhistopathological analysis, and macroscopic images were taken once thedevice was retrieved to study any possible mucosal damage. Blood sampleswere obtained from an external mammary vein on the ventral surface ofthe pig at indicated time points. Serum samples were separated fromblood by centrifugation (3220 rpm, 10 min at 4° C.) and were stored at−80° C. for further analysis.

Manufacturing and Evaluation of the Retrieval Device

The retrieval device was constructed using three 4.76 mm diameter×4.76mm length cylindrical neodymium magnets with pull force of 10.14 Newtons(K&J Magnetics, Inc.) and an Allegro A1324 linear Hall effect sensor(Modern Device), all housed in a 1-meter long Tygon tube (InnerDiameter×Outer Diameter: 4.76×6.35 mm). The sensor and magnets wereplaced on one end of the Tygon tube, with the sensing face of the sensorbent at a 45-degree angle relative to the magnets. Each pin of thesensor was soldered to a 26-gauge, solid electrical wire (AdafruitIndustries LLC) and covered in heat shrink tubing to avoid shorting thesensor. A thin layer of Med3-4213 silicone adhesive was applied at thetip of the outermost magnet to give the magnets a slight downward offsetfrom the top surface of the tubing and keep the magnets of the retrievaldevice slightly separated from the magnet of the drug delivery deviceupon connection. An Arduino Pro Mini 328 (SparkFun Electronics) receivedthe output of the Hall effect sensor and sent a text output to aserial-enabled liquid crystal display (SparkFun Electronics). When themagnets of the retrieval device connected with the magnet of the GRS,defined by a Hall effect sensor output that exceeded a given voltagethreshold for at least one minute, the liquid crystal display showed themessage “The magnets are connected.” A 3.7 V lithium ion battery(SparkFun Electronics) powered the microcontroller circuit.

The stability of the Allegro A1324 Hall effect sensor was tested in airfirst and then after immersion in simulated gastric fluid, USP withoutpepsin (pH ˜1.2; henceforth referred to as SGF). The sensing area of theinsulated sensors was covered with two-part epoxy (Devcon). Theinsulated sensor was placed in 4 mL of SGF for 90 minutes and thenremoved. After this period, the sensors and a 4.76 mm×4.76 mmcylindrical neodymium magnet were fixed in place, with 10 mm separatingthe sensing face of the sensor and the south pole of the magnet. Thesensor voltage output was read and recorded via the Arduino integrateddevelopment environment serial monitor to compare with the voltage readprior to immersion in SGF.

For in vivo evaluation of the retrieval device interaction with the GRS,the animals were sedated, intubated, and maintained with isoflurane asdescribed above. The GRS was first deployed in the stomach via anendoscopic guided overtube, and radiographs confirmed placement of thedevice in the gastric cavity. The retrieval device was then insertedinto the overtube without endoscopic guidance to demonstrate the abilityof the Hall effect sensor on the retrieval device to detect the magneton the GRS. Radiographs were captured of the retrieval device as itentered the gastric cavity, contacted the GRS as indicated on the liquidcrystal display board, and successfully retrieved the GRS.

In Vitro Stomach Model

A three-dimensional (3D) model mimicking the human stomach was designedin SolidWorks (Dassault Systemes) and created to analyze feasibility ofthe delivery and retrieval of the GRS. The 3D part was split into twohalves and then printed on a Stratasys Objet30 3D printer. Polyethyleneterephthalate (PETG) sheets from McMaster-Carr with 3.175 mm thicknesswere formed around the stomach halves using a heat gun. A band saw (HomeDepot) was used to trim the excess material away, leaving the PETG halfstomach with a 25.4 mm border. The outline of the stomach shape designedon SolidWorks was used to generate a custom gasket for sealing the twohalves of the in vitro model together. Two of these gaskets were lasercut out of 1.59 mm thick silicon rubber sheets (McMaster-Carr) using aUniversal Laser Systems VLS6.60 and then glued onto each of the stomachhalves with cyanoacrylate (Krazy Glue). About every 5 cm, clearanceholes for M6 bolts (McMaster-Carr) were drilled around the perimeter ofboth halves.

The nasal passage, pharynx, and esophagus were modelled out of a0.6-meter long PETG tubing (Inner Diameter×Outer Diameter: 9.525×12.7mm) from McMaster-Carr. The tubing was bent with a heat gun to form a90-degree turn. To interface the tubing into one stomach half, a customadapter was printed using a Formlabs Form 2 3D printer. The bottom endof the tubing was heated with a heat gun and press fit into the adapter.The upper section of the stomach half was also heated using a heat gunand fitted with the other side of the adapter. The two halves of thestomach were aligned, and 13 M6 bolts were used to secure the halvestogether and make the stomach model water tight.

Drug Release In Vitro

Individual pills made of drug-VPS for doxycycline hyclate, isoniazid,ethambutol, pyrazinamide, moxifloxacin were used to evaluate long-termrelease kinetics in SGF. Pill formulations were incubated in a NewBrunswick Innova 44 shaking incubator (Eppendorf) at 37° C. and 200 rpmin 50 mL of SGF for up to 28 days, with solution exchanges at specifiedtime intervals. Drug concentrations were then analyzed using aHigh-Performance Liquid Chromatography (HPLC). Because of the lack of avalidated HPLC method for evaluating isoniazid in SGF, water was used tostudy differences between isoniazid formulations. Three intactrifampicin devices were fabricated by loading 2 grams of drug into VPSpills. The devices were incubated in 500 mL of nanopure water for up to26 days in a shaking incubator at 37° C. and 200 rpm, with mediaexchange at specified time intervals. Water was used as a solvent forthe drug release study because rifampicin generally rapidly degrades inacid. The drug concentrations samples were then measured on an InfiniteM200Pro (Tecan) reader (absorbance, 475 nm).

High-Performance Liquid Chromatography

An Agilent 1260 Infinity II HPLC system (Agilent Technologies, Inc.)equipped with a Model 1260 quaternary pump, Model 1260 High Performanceautosampler, Model 1260 thermostat, Model 1260 Infinity ThermostattedColumn Compartment control module, and Model 1260 diode array detectorwas utilized. Data processing and analysis was performed using OpenLabCDS ChemStation (Agilent Technologies, Inc.). All solvents used werepurchased from Sigma-Aldrich Corporation. For doxycycline hyclate,chromatographic isocratic separation was carried out on an Agilent4.6×50 mm AdvanceBio RP-mAb SB-C8 analytical column with 3.5 μmparticles, maintained at 55° C. The optimized mobile phase consisted of20 mM dipotassium phosphate buffer and acetonitrile (pH 6 adjusted withtriethylamine) [60:40 (v/v)] at a flow rate of 0.85 mL/min over a 4 minrun time. The injection volume was 5 μl, and the selected ultraviolet(UV) detection wavelength was 293 nm.

For isoniazid and pyrazinamide, chromatographic isocratic separationswere carried out on an Agilent 4.6×150 mm ZORBAX Eclipse Plus C-18analytical column with 5 particles, maintained at 30° C. The optimizedmobile phase consisted of 10 mM sodium dibasic phosphate buffer andacetonitrile (pH 6.75 adjusted with phosphoric acid) [95:5 (v/v)] at aflow rate of 1.00 mL/min over a 6 min run time. The injection volume forboth drugs was 20 μl, and both drugs were analyzed using a UV detectionwavelength of 238 nm. For moxifloxacin, chromatographic separation wascarried out on an Agilent 4.6×50 mm Poroshell 120 EC-C18 analyticalcolumn with 2.7 μm particles, maintained at 50° C. The optimizedgradient consisted of nano-pure water and acetonitrile starting at [95:5(v/v)] at 0 minutes then ramping to [50:50 (v/v)] at 2.5 minutes anddescending to [95:5 (v/v)] by 5 minutes. A constant flow rate wasmaintained at 1.00 mL/min, and a post-run of 1 minute was utilized. Theinjection volume was 5 μl, and the UV detection wavelength of 293 nm wasselected.

For ethambutol, chromatographic separation was achieved using a methoddescribed previously. A Waters 3.9×300 mm μBondapak C18 analyticalcolumn with 10 μm particles, maintained at 35° C., was utilized in anisocratic elution method. The optimized mobile phase consisted ofbuffered nano-pure water (1.0 mM Cu(II)SO4, 4 g sodium1-heptanesulfonate, titrated to pH 4.50 with 10 mM HCl) andtetrahydrofuran [75:25 (v/v)]. A constant flow rate was maintained at1.50 mL/min for 15 minutes, and a post-run of 1 minute was utilized. Theinjection volume was 20 μl, and the ultraviolet (UV) detectionwavelength of 260 nm was selected.

Liquid Chromatography-Tandem Mass Spectrometry

Drug concentrations in serum from in vivo experiments were analyzedusing Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry(UPLC-MS/MS). Analysis was performed with a Waters ACQUITY UPLC-I-ClassSystem aligned with a Waters Xevo-TQ-S mass spectrometer (WatersCorporation). Liquid chromatographic separation was performed on anAcquity UPLC Charged Surface Hybrid C18 (50 mm×2.1 mm, 1.7 μm particlesize) column at 50° C. The mobile phase consisted of aqueous 0.1% formicacid, 10 mM ammonium formate solution (Mobile Phase A) and acetonitrile:10 mM ammonium formate, 0.1% formic acid solution (95:5 v/v) (MobilePhase B). The mobile phase had a continuous flow rate of 0.6 mL/minusing a time and solvent gradient composition. For the analysis ofdoxycycline hyclate, the initial composition (100% Mobile Phase A) washeld for 1 minute, following which the composition was changed linearlyto 50% Mobile Phase A over the next 0.25 minutes. At 1.5 minutes, thecomposition was 20% Mobile Phase A. At 2.5 minutes, the composition was0% Mobile Phase A and 100% Mobile Phase B, which was held constant until3 minutes. The composition returned to 100% Mobile Phase A at 3.25minutes and was held at this composition until completion of the run,ending at 4 minutes, where it remained for column equilibration. Thetotal run time was 4 minutes. For the analysis of rifampicin, theinitial composition (95% Mobile Phase A) was held for 0.5 minutes,following which the composition was changed linearly to 15% Mobile PhaseA over the next 1.25 minutes. At 1.76 minutes, the composition was 0%Mobile Phase A and 100% Mobile Phase B, which was held constant until3.25 minutes. The composition returned to 95% Mobile Phase A at 3.50minutes and was held at this composition until completion of the run,ending at 4.50 minutes, where it remained for column equilibration. Thetotal run time was 4.5 minutes.

For both the analysis of doxycycline hyclate and rifampicin, the sampleinjection volume was 2.5 μL. The mass spectrometer was operated in themultiple reaction monitoring mode. The mass to charge transitions (m/z)used to quantitate doxycycline hyclate, demeclocycline hydrochloride,rifampicin, and rifapentine were 445.19>154.1, 465.13>154.09,823.5>151.17, and 877.55>151.18, respectively. Sample introduction andionization was by electrospray ionization (ESI) in the positiveionization mode. Waters MassLynx 4.1 software was used for dataacquisition and analysis.

Stock solutions of doxycycline hyclate, rifampicin, internal standards(IS) demeclocycline hydrochloride and rifapentine were prepared inmethanol at a concentration of 500 μg/mL. A twelve-point calibrationcurve was prepared in analyte-free, blank serum ranging from 1-5000ng/mL. 100 μL of each serum sample was spiked with 200 μL of 250 ng/mLIS in acetonitrile to elicit protein precipitation. Samples werevortexed and sonicated for 10 minutes and centrifuged for 10 minutes at13000 rpm. 200 μL of supernatant was pipetted into a 96-well platecontaining 200 μL of nanopure water. Finally, 2.5 μL was injected ontothe UPLC-ESI-MS system for analysis.

Questionnaire Study

The four approaches for improving adherence were chosen by incorporatingboth behavioral and technological interventions. Three routes ofadministration are generally compatible with multigram dosing anddeployment through the esophagus: 1) placing a nasogastric (NG) tube todeploy a GRS, 2) swallowing many capsules, and 3) drinking water-drugmixture (inspired by the recent developments in gastric residenthydrogels). These options were presented to health care providers andpatients with approximate volumes of the drug necessary. Emphasis on theneed for these routes to be administered in a TB clinic was placed tomaximize the efficacy of the directly observed treatment short course(DOTS) strategy.

Example 6

J-hook shape that can first be stretched into a straight configurationduring deployment to the stomach (FIG. 19A). Once the force is removedfrom the device, it relaxes into the pre-determined shape set by aretention frame, such as nitinol “superelastic” wire (FIG. 19B). Outsidethe wire is FDA-approved flexible tubing that is used for housing theAPI. The length of the device must be at least 28.66 cm to hold 10 gramsof API. Multiple apertures can be drilled in the tubing to allow fordrug diffusion. The retention frame must be thick enough to enable theflexible tubing to comply and form the pre-determined shape in vivo. Theends of the device are sealed with a magnetic element and siliconeadhesive. The magnetic element facilitates retrieval back through thenasogastric or endoscopic tube with retrieval devices, which we havewritten about in another disclosure.

After deployment in a large animal model, serial chest/abdominal X rayswere obtained demonstrating gastric retention. FIG. 19C shows the devicein the stomach of a large animal on the first day of deployment. FIG.19D shows the same device in the stomach of a large animal 60 days afterdeployment, thus demonstrating gastric retention.

Example 7

Sphere shape that can first be stretched into a straight configurationduring deployment to the stomach (FIG. 20A). Once the force is removedfrom the device, it relaxes into the pre-determined shape set by aretention frame, such as nitinol “superelastic” wire (FIG. 20B). Outsidethe wire is FDA-approved tubing that is used for housing the API. Thelength of the device must be at least 28.66 cm to hold 10 grams of API.Multiple apertures can be drilled in the tubing to allow for drugdiffusion. The retention frame must be thick enough to enable theflexible tubing to comply and form the pre-determined shape in vivo. Theends of the device are sealed with a magnetic element and siliconeadhesive. The magnetic element facilitates retrieval back through thenasogastric or endoscopic tube with retrieval devices, which we havewritten about in another disclosure.

Example 8

In another implementation shown in FIG. 21A, a series of circles can bearranged in a three-dimensional fashion to make a cylindrical shapeddevice. Outside the wire is FDA-approved flexible tubing that is usedfor housing the API. The length of the device must be at least 28.66 cmto hold 10 grams of API. Multiple apertures can be drilled in the tubingto allow for drug diffusion. The retention frame must be thick enough toenable the flexible tubing to comply and form the pre-determined shapein vivo. The ends of the device are sealed with a magnetic element andsilicone adhesive. The magnetic element facilitates retrieval backthrough the nasogastric or endoscopic tube with retrieval devices, whichwe have written about in another disclosure.

After deployment in a large animal model, serial chest/abdominal X rayswere obtained demonstrating gastric retention. FIG. 21B shows the devicein the stomach of a large animal on the first day of deployment. FIG.21C shows the same device in the stomach of a large animal 184 daysafter deployment, thus demonstrating gastric retention.

Example 9

FIG. 22 shows another structure that assembles into a toroid-inspiredshape. Outside the wire is FDA-approved flexible tubing that is used forhousing the API. The length of the device must be at least 28.66 cm tohold 10 grams of API. Multiple apertures can be drilled in the tubing toallow for drug diffusion. The retention frame must be thick enough toenable the flexible tubing to comply and form the pre-determined shapein vivo. The ends of the device are sealed with a magnetic element andsilicone adhesive. The magnetic element facilitates retrieval backthrough the nasogastric or endoscopic tube with retrieval devices, whichwe have written about in another disclosure.

Example 10

FIG. 23 shows an exemplary route of administration of articles describedherein to a location internal to a subject. For example, the article maybe (1) administered via a transesophageal route having a firstshape/configuration where, upon removal of an elastic wire, it (2)obtains a second shape/configuration. (3-4) A therapeutic agent may bereleased from the article as it resides in the location internal to thesubject. At a desired time (5-6) the article may be retrieved viatransesophageal retrieval.

Example 11

The retrieval system was constructed using a 3/16 inch cylindricalneodynium magnet and a Allegro A1324 linear hall effect sensor allhoused in Tygon tubing with outer diameter ¼ inch and inner diameter of3/16 inch (FIG. 24A). The sensor has 3 pins, and each pin is soldered toa 26 gauge, solid electrical wire. The electrical wires are all coveredwith 0.045 inch inner diameter miniature heat shrink tubing to avoidshorting the sensor. A 5 Volt battery was used to power the sensor. AnArduino Uno aws used to provide meaningful output to the user on whenthe magnet of the retrieval system is connected with the magnet of thegastric resident system, so the LCD could display “The magnets areconnected.”

The retrieval system successfully retrieved gastric resident systems 3times. A cylindrical gastric resident system was administered to a largeanimal (FIG. 24B). It had 2 magnets, one on each side. The retrievalsystem was then inserted through an esophageal overtube (FIG. 24C), itmade contact with the magnet on the cylindrical gastric resident (FIG.24D) and then the LCD display indicated the magnets are connected, andthe gastric resident system was successfully retrieved through theovertube by the retrieval system (FIG. 1E).

Example 12

In another design, the retrieval system incorporated a fishing hook-typedesign. It used barbs made of 0.01 inch diameter nitinol wire to lift upa gastric resident system (FIGS. 25A-25C). The retrieval system has tworing neodymium magnets with ¼ inch outer diameter and 1/16 inch innerdiameter and a Allegro A1324 linear hall effect sensor all housed inTygon tubing with outer diameter ¼ inch and inner diameter of 3/16 inch(FIG. 25D). The barbs are only extended out of the retrieval system oncethe retrieval system has made contact with the drug delivery system.FIG. 25D shows the retrieval system with the barbs extended out. FIG.25E shows successful contact and retrieval of the retrieval system withbarbs.

The barbs are made of 0.01 inch diameter nitinol that can cooked on afixture at 500 degrees Fahrenheit for 20 minutes and then quenches incold water. The fixture has pins and bolts positioned in a manner thatallows the nitinol to be cooked at various bend angles. The angle of thebarbs (FIG. 26A) may be chosen depending on the maximum impulse forlifting a gastric resident system. Instron testing was done to determinethe impulse for barb angles ranging from 13.5 to 27.7 degrees, with 20.3degrees being the optimal barb angle (FIG. 26B).

The sensor has 3 pins, and each pin is soldered to a 26 gauge, solidelectrical wire. The electrical wires are all covered with 0.045 inchinner diameter miniature heat shrink tubing to avoid shorting thesensor. A 5 Volt battery is used to power the sensor. An Arduino Uno isused to provide meaningful output to the user on when the magnet of theretrieval system is connected with the magnet of the gastric residentsystem, so the LCD can display “The magnets are connected.”

Example 13

In another implementation shown in FIG. 27A, the retrieval systemincorporates a single-oval polypectomy snare in addition to a series ofring neodymium magnets with ¼ inch outer diameter and 1/16 inch innerdiameter and Allegro A1324 linear hall effect sensor all housed in Tygontubing with outer diameter ¼ inch and inner diameter of 3/16 inch. Thesnare is only activated to expand once the retrieval system is incontact with the magnet of the gastric resident system. The snare canhold a weigh of at least 200 grams as shown in FIG. 27B.

The sensor has 3 pins, and each pin is soldered to a 26 gauge, solidelectrical wire. The electrical wires are all covered with 0.045 inchinner diameter miniature heat shrink tubing to avoid shorting thesensor. A 5 Volt battery is used to power the sensor. An Arduino Uno isused to provide meaningful output to the user on when the magnet of theretrieval system is connected with the magnet of the gastric residentsystem, so the LCD can display “The magnets are connected.”

Exemplary Embodiments

-   -   1. An article with the capacity for sustained drug delivery in a        mammal capable of transesophageal administration and        transesophageal retrieval composing of a series of drug delivery        systems attached to a superelastic retention frame        -   a. Wherein the article components are made of biocompatible            materials        -   b. Wherein the drug delivery article can safely reside in            the stomach with a gastric retentive component        -   c. Wherein the article is capable of minimizing burst            release of drug    -   2. The article according to embodiment 1 wherein the article has        the capacity to retain its final shape while stored for 1-365        days.    -   3. The article according to embodiment 1 where the article is        composed of a retention frame which is composed of but not        limited to:        -   a. Low modulus elastomer wire such as silicone or            polyurethane        -   b. Elastic wire such as a superelastic alloy or other shape            memory material like nitinol        -   c. Hollow heat-shaped elastomer tubing        -   d. Hollow shape-memory alloy    -   4. The article according to embodiment 1 where the drug delivery        system is made of series of cylindrical pills made of drug mixed        with a nonerodable matrix such as vinylpolysiloxane,        polydimethylsiloxane, polycaprolactone, polyethylene, or        polyethylene-vinyl acetate, and each pill has a 0.5 mm hole        inside it.    -   5. The article according to embodiment 1 and embodiment 4 where        the drug is doxycycline hyclate, moxifloxacin, pyrazinamide,        isoniazid, or moxifloxacin.    -   6. The article according to embodiment 1 and 4 where the        diameter of the cylindrical pills is 4 mm and the height is more        than 5 mm    -   7. The article according to embodiment 1 and 4 where the        diameter of the cylindrical pills is 4 mm and the height is more        than 5 mm    -   8. The article according to embodiment 1 and 4 where the pills        are coated with Eudragit RS PO, Eudragit NM 30D,        polycaprolactone, ethylcellulose, cellulose acetate, cellulose        acetate butyrate, polydimethysiloxane, or vinylpolysiloxane.    -   9. The article according to embodiment 1 and 4 where the pills        have 2 or more drug powders in them.    -   10. The article according to embodiment 1 and 4 where the pills        contain excipients such as polyethylene glycol to tune the        release rate of the drug.    -   11. The article according to embodiment 1 where the drug        delivery system is made of series of cylindrical pills made of        concentric cylinders with each a different concentration of drug        in each cylinder and made of drug mixed with vinylpolysiloxane,        polydimethylsiloxane, polycaprolactone, polyethylene, or        polyethylene-vinyl acetate, and each pill has a 0.5 mm hole        inside it.    -   12. The article according to embodiment 1 and embodiment 11        where the drug is doxycycline hyclate, moxifloxacin,        pyrazinamide, isoniazid, or moxifloxacin.    -   13. The article according to embodiment 1 and 11 where the        diameter of the cylindrical pills is 4 mm and the height is more        than 5 mm    -   14. The article according to embodiment 1 and 11 where the        diameter of the cylindrical pills is 4 mm and the height is more        than 5 mm    -   15. The article according to embodiment 1 and 11 where the pills        are coated with Eudragit RS PO, Eudragit NM 30D,        polycaprolactone, ethylcellulose, cellulose acetate, cellulose        acetate butyrate, polydimethysiloxane, or vinylpolysiloxane.    -   16. The article according to embodiment 1 and 11 where the pills        have 2 or more drug powders in them.    -   17. The article according to embodiment 1 and 11 where the pills        contain excipients such as polyethylene glycol to tune the        release rate of the drug.    -   18. The article according to embodiment 1 where the drug        delivery system is made of series of cylindrical pills made of        hollow flexible tubing enclosing the drug powder, retention        frame, and has micro-drilled holes in the tubing to facilitate        drug release    -   19. The article according to embodiment 1 and embodiment 18        where the drug is doxycycline hyclate, moxifloxacin,        pyrazinamide, isoniazid, or moxifloxacin.    -   20. The article according to embodiment 1 and embodiment 18        where the micro-drilled hole have porous thin polymer films to        control the rate of drug release.    -   21. The article according to embodiment 1 where the retention        frame and pills are enclosed in flexible tubing that may be        permeable to fluid or impermeable to fluid and have holes to        allow access to fluid.    -   22. The article according to embodiment 1 where the retention        frame is immersed in silicone adhesive at both ends.    -   23. The article according to embodiment 1 where the article has        a magnetic bead on one or both ends to facilitate retrieval via        nasogastric or endoscopic tube.    -   24. The article according to embodiment 1 where the article        shape can be fitted inside a nasogastric or endoscopic tube as        well as standard larger feeding tubes for veterinary use.    -   25. An article with the capacity for drug delivery in a mammal        having gastric retention for greater than 1 month:    -   a. Wherein the article is compatible with transesophageal        administration through a nasogastric or endoscopic tube.    -   b. Wherein the article is of dimensions compatible with gastric        retention.    -   c. Wherein the article is at least 28.66 cm long to hold at        least 10 grams of API.    -   d. Wherein the article is compatible with transesophageal        retrieval through a nasogastric or endoscopic tube.    -   26. The article according to embodiment 25 wherein the article        has the capacity to retain its final shape while stored for        1-365 days.    -   27. The article according to embodiment 25 wherein the article        shape can be stretched into a straight configuration while being        administered and then revert to an altered shape of a J-hook        with a minimum diameter of 2 cm when it reaches the stomach.    -   28. The article according to embodiment 25 wherein the article        shape can be stretched into a straight configuration while being        administered and then revert to an altered shape of a sphere        with a minimum diameter of 2 cm when it reaches the stomach.    -   29. The article according to embodiment 25 wherein the article        shape can be stretched into a straight configuration while being        administered and then revert to an altered shape of a series of        circles like a cylinder with a minimum diameter of the circle        being 2 cm when it reaches the stomach.    -   30. The article according to embodiment 25 wherein the article        shape can be stretched into a straight configuration while being        administered and then revert to an altered shape of a toroid        with a minimum diameter of 2 cm of the circular sections when it        reaches the stomach.    -   31. The article according to embodiment 25 where the maximum        force to administer the article through a nasogastric or        endoscopic tube is 20 N.    -   32. The article according to embodiment 25 where the article is        composed of a retention frame which is composed of but not        limited to:    -   a. Low modulus elastomer wire such as silicone or polyurethane    -   b. Elastic wire such as a superlastic alloy or other shape        memory material    -   c. Hollow heat-shaped elastomer tubing    -   d. Hollow shape-memory alloy    -   33. The article according to embodiment 25 and 32 where the        retention frame is encapsulated inside an elastomeric hollow        tubing, which has a cross-section of a circle, cube, triangle,        and other polygons.    -   34. The article according to embodiment 25 and 32 where the        retention frame is encapsulated inside an elastomeric        multi-lumen tubing.    -   35. The article according to embodiment 25 and 32 where the        article is made of a multi-material complex blend of a retention        wire and elastomeric tubing.    -   36. The article according to embodiment 25 and 32 where the        retention frame is on the outside of the elastomeric tubing.    -   37. The article according to embodiment 25 and 32 where the        retention frame is immersed in silicone adhesive and besides a        magnetic bead.    -   38. The article according to embodiment 25 where the article has        a magnetic bead on one or both ends to facilitate retrieval via        nasogastric or endoscopic tube.    -   39. The article according to embodiment 25 where the maximum        force to retrieve the article through a nasogastric or        endoscopic tube is 20 N.    -   40. The article according to embodiment 25 where the article        shape can be fitted inside a nasogastric or endoscopic tube as        well as standard larger feeding tubes for veterinary use.    -   41. A magnetic retrieval system for use in a large mammal:        -   a. Wherein the system is compatible with transesophageal            passage through a nasogastric or endoscopic tube.        -   b. Wherein the system has dimensions compatible with access            to the stomach        -   c. Wherein the system has a sensor element to detect the            distance from a magnet on the gastric resident system        -   d. Wherein the system has a magnet to attach to the gastric            resident system        -   e. Wherein the system has an output signal for the user to            indicate contact of the retrieval system with the gastric            resident system        -   f. Wherein the system can hold the weight and retrieve the            gastric resident system    -   42. The system according to embodiment 41 wherein the system        uses flexible tubing with outer diameter less than ¼ inch to        house the sensor and magnet.    -   43. The system according to any one of embodiments 41-42 wherein        the system uses a Hall effect sensor.    -   44. The system according to any one of embodiments 41-43 wherein        the system uses cylindrical or ring magnets with maximum outer        diameter of 3/16 inches.    -   45. The system according to any one of embodiments 41-44 wherein        the system uses barbs.    -   46. The system according to any one of embodiments 41-45 wherein        the system uses a LCD display, LED lights, or sound to indicate        the distance of the retrieval system from the gastric resident        system.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

Any terms as used herein related to shape, orientation, alignment,and/or geometric relationship of or between, for example, one or morearticles, structures, forces, fields, flows, directions/trajectories,and/or subcomponents thereof and/or combinations thereof and/or anyother tangible or intangible elements not listed above amenable tocharacterization by such terms, unless otherwise defined or indicated,shall be understood to not require absolute conformance to amathematical definition of such term, but, rather, shall be understoodto indicate conformance to the mathematical definition of such term tothe extent possible for the subject matter so characterized as would beunderstood by one skilled in the art most closely related to suchsubject matter. Examples of such terms related to shape, orientation,and/or geometric relationship include, but are not limited to termsdescriptive of: shape—such as, round, square, gomboc, circular/circle,rectangular/rectangle, triangular/triangle, cylindrical/cylinder,elliptical/ellipse, (n)polygonal/(n)polygon, etc.; angularorientation—such as perpendicular, orthogonal, parallel, vertical,horizontal, collinear, etc.; contour and/or trajectory—such as,plane/planar, coplanar, hemispherical, semi-hemispherical, line/linear,hyperbolic, parabolic, flat, curved, straight, arcuate, sinusoidal,tangent/tangential, etc.; direction—such as, north, south, east, west,etc.; surface and/or bulk material properties and/or spatial/temporalresolution and/or distribution—such as, smooth, reflective, transparent,clear, opaque, rigid, impermeable, uniform(ly), inert, non-wettable,insoluble, steady, invariant, constant, homogeneous, etc.; as well asmany others that would be apparent to those skilled in the relevantarts. As one example, a fabricated article that would described hereinas being “square” would not require such article to have faces or sidesthat are perfectly planar or linear and that intersect at angles ofexactly 90 degrees (indeed, such an article can only exist as amathematical abstraction), but rather, the shape of such article shouldbe interpreted as approximating a “square,” as defined mathematically,to an extent typically achievable and achieved for the recitedfabrication technique as would be understood by those skilled in the artor as specifically described. As another example, two or more fabricatedarticles that would described herein as being “aligned” would notrequire such articles to have faces or sides that are perfectly aligned(indeed, such an article can only exist as a mathematical abstraction),but rather, the arrangement of such articles should be interpreted asapproximating “aligned,” as defined mathematically, to an extenttypically achievable and achieved for the recited fabrication techniqueas would be understood by those skilled in the art or as specificallydescribed.

1. A system configured for transesophageal retrieval, comprising: apolymeric component having a flexible member; a binding componentassociated with an end portion of the polymeric component; and a sensorassociated with an end portion of the polymeric component, wherein thesystem is configured to pass through a nasogastric and/or endoscopictube.
 2. A system as in claim 1, wherein the binding component comprisesa magnet.
 3. A system as in claim 1, wherein the binding componentcomprises a first species configured to interact with a second speciesvia a binding event.
 4. A system as in claim 1, wherein the system isconfigured to magnetically associate with a gastric residence system. 5.A system as in claim 1, wherein the sensor is configured to determine adistance between the binding component and a second component.
 6. Asystem as in claim 5, wherein the sensor is a Hall effect sensor.
 7. Asystem as in claim 1, wherein the system is configured to maintaincontact with a gastric residence system during extraction of saidgastric residence system from a location internal to a subject.
 8. Asystem as in claim 1, wherein the polymeric component comprises aflexible tube.
 9. A system as in claim 1, wherein the system has amaximum diameter less than or equal to 7 mm.
 10. A system as in claim 1,further comprising a locking mechanism.
 11. A system as in claim 10,wherein the locking mechanism comprises a snare.
 12. A system as inclaim 10, wherein the locking mechanism comprises a plurality of barbedfeatures.
 13. A method for retrieving a gastric residence system locatedinternal to a subject, comprising: administering transesophageally to asubject a system, the system comprising a polymeric component having aflexible member and a binding component associated with an end portionof the polymeric component; determining, via a sensor associated with anend portion of the polymeric component, a distance between the bindingcomponent and the gastric residence system; interfacing, via a lockingmechanism associated with an end portion of the polymeric component, thegastric residence system; and removing, transesophageally, the gastricresidence system from the location internal to the subject.